Hepatorenal Syndrome (HRS) is progressive renal failure associated with liver cirrhosis or fulminant liver failure. It is a life-threatening condition in which kidney function rapidly declines resulting in >50% mortality in ≦6 months. HRS occurs in 18% of cirrhotic patients within one year of diagnosis and in 39% of patients within five years. Based on the speed of progression of renal failure, as measured by serum creatinine level, HRS is categorized into two types. Type 1 HRS is the more rapidly progressing type and is characterized by a 100% increase in serum creatinine to >2.5 mg/dL within two weeks. Less than 10% survive hospitalization, and the median survival is only two weeks. Type 2 HRS is slower progressing, with serum creatinine rising gradually. However, type 2 HRS patients can develop sudden renal failure and become diagnosed with type 1 HRS. Although HRS can occur spontaneously, other common precipitating factors are bacterial infections, gastrointestinal hemorrhage, therapeutic paracentesis, etc.
Deteriorating liver function is believed to be the underlying cause of changes in the circulation to the viscera, altering blood flow and blood vessel tone in the kidneys. The renal failure in HRS is a consequence of these changes in blood flow. The presence of elevated pressure in the portal vein (portal hypertension) in patients with liver damage is thought to result in secretion of vasodilator substances in the splanchnic circulation that causes systemic arterial underfilling. This hypotensive state triggers vasoconstriction in the kidney as a means to restore systemic blood pressure. However, the effect of this restoration is insufficient to counteract the mediators of vasodilation in circulation, leading to persistent “underfilling” of the renal circulation and worsening renal vasoconstriction, leading to renal failure.
HRS is thought to be part of a spectrum of illness associated with increased pressure in the portal vein circulation, which begins with the development of fluid in the abdomen (ascites). Ascites is a major complication associated with HRS and is exacerbated by impaired sodium excretion. The spectrum continues with diuretic-resistant ascites, where the kidneys are unable to excrete sufficient sodium to clear the fluid even with the use of diuretic medications. Most individuals with type 2 HRS have diuretic-resistant ascites before they develop deterioration in kidney function.
Liver transplantation is the only available cure for HRS; however, most patients do not live long enough to have the procedure. Currently available treatment for HRS is largely supportive and administered in an effort to bridge the patient to transplantation. Volume support with salt-poor albumin is the mainstay of treatment, as HRS patients have chronic total body sodium overload despite low serum sodium levels and hypotension. Use of vasoconstrictors, such as terlipressin or vasopressin, is thought to be effective by restoring pressure in the vasodilated splanchnic circulation. However, the adverse effects of reduced organ perfusion and marginal effect on sodium excretion limit their utility (Gines, P., et al., Hepatorenal syndrome. Lancet, 2003. 362(9398): p. 1819-27; Lata, J., Hepatorenal syndrome. World J Gastroenterol, 2012. 18(36): p. 4978-84; Salerno, F., et al., Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut, 2007. 56(9): p. 1310-8). Therefore, there is an urgent need for new agents to improve renal function at least sufficient to help support patients prior to transplantation.